Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.079
Filtrar
1.
J Phys Chem Lett ; : 8982-8990, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34506716

RESUMO

For ternary organic solar cells (T-OSCs), introducing the third component (D2) can significantly enhance the efficiency of cell while still maintaining easy fabrication. However, it brings difficulty in physical understanding of the fundamental mechanism because of the more complicated photophysical processes in T-OSCs. Accordingly, how the guest donor D2 regulates the charge transfer mechanism was explored in theory using three T-OSCs containing two donors and an acceptor. The results point out that larger differences in molecular weight and/or backbone between D2 and the host donor D1 cause different charge transfer mechanisms, which hardly provide a coexisting charge transfer path. Besides, strong absorption capacity of D2 with a high oscillator strength would produce favorable regulation of the charge transfer mechanism. Therefore, this work clarifies the influence of D2 on the charge transfer mechanism in T-OSCs, which suggests that the method of improving the power conversion efficiency cannot be generalized but rather must be tailored to specific conditions.

2.
Biosci Rep ; 41(9)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34467977

RESUMO

OBJECTIVE: Renal cell carcinoma is prone to early metastasis. In general, intraocular metastasis (IOM) is not common. In the present study, we studied the relationship between different biochemical indicators and the occurrence of IOM in renal cancer patients, and identified the potential risk factors. METHODS: A retrospective analysis of the clinical data of 214 patients with renal cell carcinoma from October 2001 to August 2016 was carried out. The difference and correlation of various indicators between the two groups with or without IOM was analyzed, and binary logistic regression analysis was used to explore the risk factors of IOM in renal cancer patients. The diagnostic value of each independent related factor was calculated according to the receiver operating curve (ROC). RESULTS: The level of neuron-specific enolase (NSE) in renal cell carcinoma patients with IOM was significantly higher than that in patients without IOM (P<0.05). There was no significant difference in alkaline phosphatase (ALP), hemoglobin (Hb), serum calcium concentration, α fetoprotein (AFP), carcinoembryonic antigen (CEA), CA-125 etc. between IOM group and non-IOM (NIOM) group (P>0.05). Binary logistic regression analysis showed that NSE was an independent risk factor for IOM in renal cell carcinoma patients (P<0.05). ROC curve shows that the factor has high accuracy in predicting IOM, and the area under the curve (AUC) is 0.774. The cut-off value of NSE was 49.5 U/l, the sensitivity was 72.2% and the specificity was 80.1%. CONCLUSION: NSE concentration is a risk factor for IOM in patients with renal cell cancer. If the concentration of NSE in the patient's body is ≥49.5 U/l, disease monitoring and eye scans should be strengthened.

3.
Biosens Bioelectron ; 194: 113611, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34500229

RESUMO

The high toxicity of dicofol (DICO) to nontarget organisms has resulted in the contamination of food materials and caused a threat to human health. Developing a rapid and sensitive detection method of DICO in food samples is essential and still pursued. Fluorescent nanomaterials have been widely applied in biosensors to improve the sensitivity of detection. Herein, glutathione-capped Au-Ag bimetallic nanoclusters (Au-Ag NCs) exhibited the outstanding fluorescence characteristic with the average fluorescence lifetime of 1971.08 ns and photoluminescence quantum yield of 9.84% when the molar ratio of Au to Ag was 5:1. Polyethyleneimine modified gold nanoparticles (PEI-Au NPs) with the positive charge were prepared to generate a strong colorimetric signal. A dual-model colorimetric/fluorescent immune probe based on the Au-Ag NCs and PEI-Au NPs was successfully constructed by electrostatic force, and could be applied in both ic-ELISA and LFIA methods for rapid and ultrasensitive detection of DICO. In the ic-ELISA method, the introduction of fluorescence signal significantly increased the sensitivity of detection with the limit of detection (LOD) of 0.62 ng/mL and exhibited an excellent linear relationship within the range of 1.36 ng/mL-19.92 ng/mL. In the LFIA method, the fluorescence signal of Au-Ag NCs was accumulated on the test line and control line for the fluorescence model detection with a quantitative LOD at the level of 1.59 ng/mL. Such a dual-model colorimetric/fluorescent immunoassay serves as a promising candidate to develop new approaches in field detection.

4.
Neurosci Bull ; 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34523068

RESUMO

A large number of putative risk genes for autism spectrum disorder (ASD) have been reported. The functions of most of these susceptibility genes in developing brains remain unknown, and causal relationships between their variation and autism traits have not been established. The aim of this study was to predict putative risk genes at the whole-genome level based on the analysis of gene co-expression with a group of high-confidence ASD risk genes (hcASDs). The results showed that three gene features - gene size, mRNA abundance, and guanine-cytosine content - affect the genome-wide co-expression profiles of hcASDs. To circumvent the interference of these features in gene co-expression analysis, we developed a method to determine whether a gene is significantly co-expressed with hcASDs by statistically comparing the co-expression profile of this gene with hcASDs to that of this gene with permuted gene sets of feature-matched genes. This method is referred to as "matched-gene co-expression analysis" (MGCA). With MGCA, we demonstrated the convergence in developmental expression profiles of hcASDs and improved the efficacy of risk gene prediction. The results of analysis of two recently-reported ASD candidate genes, CDH11 and CDH9, suggested the involvement of CDH11, but not CDH9, in ASD. Consistent with this prediction, behavioral studies showed that Cdh11-null mice, but not Cdh9-null mice, have multiple autism-like behavioral alterations. This study highlights the power of MGCA in revealing ASD-associated genes and the potential role of CDH11 in ASD.

5.
Aging (Albany NY) ; 13(undefined)2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34516404

RESUMO

OBJECTIVE: To investigate the changes of amplitude of low-frequency fluctuation (ALFF) in brain regions of patients with hypertensive retinopathy by using resting-state functional magnetic resonance imaging (rs-fMRI) and change in the relationship of ALFF value with potential emotional and psychological changes. METHODS: Thirty-one patients with hypertensive retinopathy (HR) (16 men and 15 women) and 31 healthy controls (HCs; 16 men and 15 women) matched for age, sex, and weight were enrolled in the research. The changes in mean ALFF values could reflect brain activity between HR patients and HCs. We used the independent samples t-test to evaluate different demographic and general information between the two groups. Two-sample t-test was used to detect differences of mean ALFF values in the brain region between the two groups using the same software. RESULTS: The ALFF values in the brain areas of HR and HCs were different. HR patients had lower ALFF value in the left medial superior frontal gyrus and left middle frontal gyrus than the HCs. The higher ALFF values were found in the cerebellum (left inferior and right superior lobes, vermis) and left inferior temporal gyrus of the HR patients than the controls. CONCLUSION: Our findings showed fluctuations in ALFF values in the HR patients' brain regions. ALFF values reflect over or reduced activity in brain regions. Abnormal ALFF values in these brain areas can predict early HR development, preventing the malignant transformation of hypertensive microangiopathy.

6.
Org Lett ; 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34519513

RESUMO

This work describes an electrochemically promoted nickel-catalyzed deoxygenative thiolation of alcohols and ketones under mild conditions. Excellent substrate tolerance and good chemical yields can be achieved by graphene/nickel foam electrodes in an undivided cell. Further study to gain mechanistic insight into this electrochemical cross-coupling has been carried out.

7.
Cancer Biol Med ; 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34491007

RESUMO

OBJECTIVE: Large volume radiological text data have been accumulated since the incorporation of electronic health record (EHR) systems in clinical practice. We aimed to determine whether deep natural language processing algorithms could aid radiologists in improving thyroid cancer diagnosis. METHODS: Sonographic EHR data were obtained from the EHR database. Pathological reports were used as the gold standard for diagnosing thyroid cancer. We developed thyroid cancer diagnosis based on natural language processing (THCaDxNLP) to interpret unstructured sonographic text reports for thyroid cancer diagnosis. We used the area under the receiver operating characteristic curve (AUROC) as the primary metric to measure the performance of the THCaDxNLP. We compared the performance of thyroid ultrasound radiologists aided with THCaDxNLP vs. those without THCaDxNLP using 5 independent test sets. RESULTS: We obtained a total number of 788,129 sonographic radiological reports. The number of thyroid sonographic data points was 132,277, 18,400 of which were thyroid cancer patients. Among the 5 test sets, the numbers of patients per set were 439, 186, 82, 343, and 171. THCaDxNLP achieved high performance in identifying thyroid cancer patients (the AUROC ranged from 0.857-0.932). Thyroid ultrasound radiologists aided with THCaDxNLP achieved significantly higher performances than those without THCaDxNLP in terms of accuracy (93.8% vs. 87.2%; one-sided t-test, adjusted P = 0.003), precision (92.5% vs. 86.0%; P = 0.018), and F1 metric (94.2% vs. 86.4%; P = 0.007). CONCLUSIONS: THCaDxNLP achieved a high AUROC for the identification of thyroid cancer, and improved the accuracy, sensitivity, and precision of thyroid ultrasound radiologists. This warrants further investigation of THCaDxNLP in prospective clinical trials.

8.
J Am Chem Soc ; 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34498856

RESUMO

Manganese complexes in +6 oxidation state are rare. Although a number of Mn(VI) nitrido complexes have been generated in solution via one-electron oxidation of the corresponding Mn(V) nitrido species, they are too unstable to isolate. Herein we report the isolation and the X-ray structure of a Mn(VI) nitrido complex, [MnVI(N)(TAML)]- (2), which was obtained by one-electron oxidation of [MnV(N)(TAML)]2- (1). 2 undergoes N atom transfer to PPh3 and styrenes to give Ph3P═NH and aziridines, respectively. A Hammett study for various p-substituted styrenes gives a V-shaped plot; this is rationalized by the ability of 2 to function as either an electrophile or a nucleophile. 2 also undergoes hydride transfer reactions with NADH analogues, such as 10-methyl-9,10-dihydroacridine (AcrH2) and 1-benzyl-1,4-dihydronicotinamide (BNAH). A kinetic isotope effect of 7.3 was obtained when kinetic studies were carried out with AcrH2 and AcrD2. The reaction of 2 with NADH analogues results in the formation of [MnV(N)(TAML-H+)]- (3), which was characterized by ESI/MS, IR spectroscopy, and X-ray crystallography. These results indicate that this reaction occurs via an initial "separated CPET" (separated concerted proton-electron transfer) mechanism; that is, there is a concerted transfer of 1 e- + 1 H+ from AcrH2 (or BNAH) to 2, in which the electron is transferred to the MnVI center, while the proton is transferred to a carbonyl oxygen of TAML rather than to the nitrido ligand.

9.
Placenta ; 114: 14-21, 2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34418750

RESUMO

INTRODUCTION: The chorioallantoic placenta is a specific organ for placental mammals. However, the adaptive events during its emergence are still poorly investigated. METHODS: We scanned the chromosome X to detect the accelerated evolution in the ancestral lineage of placental mammals, and constructed 3D protein structure models of a candidate by homology modeling. RESULTS: Eight branch-specific accelerated regions were identified. Five of these regions (P=5.61×10-11 ~ 9.03×10-8) are located in the five exons of Nik-related kinase (Nrk), which is essential in placenta development and fetoplacental induction of labor. Nrk belongs to the germinal center kinase-IV subfamily with the overall similar protein structure; however, a new exon emerged in ancestors of placental mammals and its sequence has been conserved since then. Structure modelling of NRK suggests that the accelerated exons and the placental-mammal-specific exon (as a new loop) could change the enzymatic activity and the structure of placental mammal NRK. DISCUSSION: Since the new loop is surrounded by the accelerated protein regions, it is likely that the new loop occurred and shifted the function of NRK, and then the accelerated evolution of Nrk occurred to adapt the structure change caused by the new loop in the ancestral lineage of placental mammals. Overall, this work suggests that the fundamental process of placental development and fetoplacental induction of labor has been targeted by positive Darwinian selection.

10.
Pacing Clin Electrophysiol ; 44(9): 1523-1531, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34337768

RESUMO

BACKGROUND: His bundle pacing (HBP) is a physiological pacing strategy to preserve the electrical synchrony of ventricular conduction and left ventricular (LV) function. Left bundle branch pacing (LBBP) has emerged as an alternative physiological pacing technique. OBJECTIVE: To evaluate cardiac electrical and mechanical synchrony comparing LBBP and HBP in patients with permanent atrial fibrillation (AF). METHODS: Consecutive patients with symptomatic bradycardia and AF were enrolled from January to June of 2019. The cardiac electrical and mechanical synchrony in different pacing mode were evaluated at baseline and after implantation. RESULTS: Both HBP and LBBP were performed in 20 patients. LBBP significantly widened the QRS duration compared with the intrinsic conduction (113.2 ± 14.5  vs. 96.5 ± 16.2 ms; p = .01), while HBP did not (104.5 ± 22.3  vs. 96.5 ± 16.2 ms; p = .12). Both LBBP and HBP patients had similar LV myocardial strain measurements for the mechanical synchrony evaluation without significant change compared with baseline. There was no significant difference in right ventricular synchrony measurement between LBBP and HBP. Compared to HBP, LBBP had less interventricular synchrony (IMVD, 14.7 ± 9.2  vs. 3.1 ± 12.7 ms, p < .01; Ts-LV-RV, 37.9 ± 10.7  vs. 18.5 ± 10.8 ms, p < .001). CONCLUSIONS: Although LBBP's a physiological pacing mode can achieve a similar cardiac electrical and mechanical synchronization when compared to HBP, LBBP results in modest delay in RV activation, and the clinical implication remains to be studied.

11.
J Biomed Sci ; 28(1): 60, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34452635

RESUMO

BACKGROUND: Streptococcus pneumoniae is a common cause of post-influenza secondary bacterial infection, which results in excessive morbidity and mortality. Although 13-valent pneumococcal conjugate vaccine (PCV13) vaccination programs have decreased the incidence of pneumococcal pneumonia, PCV13 failed to prevent serotype 3 pneumococcal disease as effectively as other vaccine serotypes. We aimed to investigate the mechanisms underlying the co-pathogenesis of influenza virus and serotype 3 pneumococci. METHODS: We carried out a genome-wide screening of a serotype 3 S. pneumoniae transposon insertion mutant library in a mouse model of coinfection with influenza A virus (IAV) to identify the bacterial factors required for this synergism. RESULTS: Direct, high-throughput sequencing of transposon insertion sites identified 24 genes required for both coinfection and bacterial infection alone. Targeted deletion of the putative aminotransferase (PA) gene decreased bacterial growth, which was restored by supplementation with methionine. The bacterial burden in a coinfection with the PA gene deletion mutant and IAV in the lung was lower than that in a coinfection with wild-type pneumococcus and IAV, but was significantly higher than that in an infection with the PA gene deletion mutant alone. These data suggest that IAV infection alters host metabolism to benefit pneumococcal fitness and confer higher susceptibility to pneumococcal infection. We further demonstrated that bacterial growth was increased by supplementation with methionine or IAV-infected mouse lung homogenates. CONCLUSIONS: The data indicates that modulation of host metabolism during IAV infection may serve as a potential therapeutic intervention against secondary bacterial infections caused by serotype 3 pneumococci during IAV outbreaks in the future.

12.
Med Sci Monit ; 27: e930738, 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34376631

RESUMO

BACKGROUND Whether nab-paclitaxel plus carboplatin as neoadjuvant therapy can benefit patients with resectable squamous cell carcinoma of the lung remains unclear. This prospective study aimed to investigate outcomes in patients with stage IIIA-N2 squamous cell carcinoma of the lung treated with nab-paclitaxel plus carboplatin as neoadjuvant therapy. MATERIAL AND METHODS Patients with stage IIIA-N2 squamous cell carcinoma of the lung were treated with nab-paclitaxel (100 mg/m², days 1, 8, and 15) and carboplatin (5 mg/(mL·min), day 1) for two 21-day cycles. The patients were followed every 3 months for 2 years and every 6 months after that. The primary endpoint was the downstaging rate. Secondary endpoints included objective response rate (ORR), margin-free (R0) resection, pathologic complete response (pCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS Among the 36 enrolled patients, 33 completed neoadjuvant chemotherapy, and 23 underwent surgery. The preoperative ORR was 50.0% (18/36). R0 resection was achieved in 22 (95.7%) of 23 patients. Major pathologic response and pCR were achieved in 8 (34.8%) and 2 (8.7%) patients, respectively. The overall downstaging rate was 47.8% (11/23). The median follow-up was 39.8 (32.5-41.0) months. For patients who underwent surgery, the median PFS and OS were 31.4 (95%CI: 10.4-not reached (NR)) and 45.0 (95%CI: 22.6-NR) months, respectively. The most common adverse events were neutropenia, anemia, and leukopenia. CONCLUSIONS This study preliminarily indicated a favorable effect of nab-paclitaxel plus carboplatin as neoadjuvant therapy without significant adverse events for stage IIIA-N2 squamous cell carcinoma of the lung. Future randomized controlled trials are needed to verify these results.

13.
Front Immunol ; 12: 643282, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34421886

RESUMO

Background: Only a proportion of patients with bladder cancer may benefit from durable response to immune checkpoint inhibitor (ICI) therapy. More precise indicators of response to immunotherapy are warranted. Our study aimed to construct a more precise classifier for predicting the benefit of immune checkpoint inhibitor therapy. Methods: This multi-cohort study examined the top 20 frequently mutated genes in five cohorts of patients with bladder cancer and developed the TP53/PIK3CA/ATM mutation classifier based on the MSKCC ICI cohort. The classifier was then validated in a validation set consisting of IMvigor210 cohort and Broad/Dana-Farber cohort. The molecular profile and immune infiltration characteristics in each subgroup as defined by this classifier were explored. Results: Among all 881 patients with bladder cancer, the mutation frequency of TP53, PIK3CA, and ATM ranked in the top 20 mutated genes. The TP53/PIK3CA/ATM mutation classifier was constructed based on the Memorial Sloan Kettering Cancer Center (MSKCC) ICI cohort and only showed predictive value for patients with bladder cancer who received ICI therapy (median overall survival: low-risk group, not reached; moderate-risk group, 13.0 months; high-risk group, 8.0 months; P<0.0001). Similar results were found in subgroups of MSKCC ICI cohort defined by tumor mutation burden. Multivariate Cox analysis revealed that the risk group defined by the classifier served as an independent prognostic factor for overall survival in patients with bladder cancer. Efficacy of the classifier was verified in a validation set consisting of IMvigor210 cohort and Broad/Dana-Farber cohort. Lower expression of PD-1/PD-L1 and less tumor immune infiltration were observed in the high-risk group than the other two groups of the TCGA cohort and the IMvigor210 cohort. Conclusion: Our study constructed a TP53/PIK3CA/ATM mutation classifier to predict the benefit of immune checkpoint inhibitor therapy for patients with bladder cancer. This classifier can potentially complement the tumor mutation burden and guide clinical ICI treatment decisions according to distinct risk levels.

14.
iScience ; : 103040, 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34462732

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic remains a source of considerable morbidity and mortality throughout the world. Therapeutic options to reduce symptoms, inflammatory response, or disease progression are limited. This randomized open-label trial enrolled 100 ambulatory patients with symptomatic COVID-19 in Toronto, Canada. Results indicate that icosapent ethyl (8g daily for 3 days followed by 4g daily for 11 days) significantly reduced high-sensitivity C-reactive protein (hs-CRP) and improved symptomatology compared with patients assigned to usual care. Specifically, the primary biomarker endpoint, change in hs-CRP, was significantly reduced by 25% among treated patients (-0.5mg/L, IQR[-6.9,0.4], within-group P=0.011). Conversely, a non-significant 5.6% reduction was observed among usual care patients (-0.1mg/L, IQR[-3.2,1.7], within-group P=0.51). An unadjusted between-group primary biomarker analysis was non-significant (P=0.082). Overall, this report provides evidence of an early anti-inflammatory effect of icosapent ethyl in a modest sample, including an initial well-tolerated loading dose, in symptomatic COVID-19 outpatients. ClinicalTrials.gov Identifier: NCT04412018.

15.
Biomed Res Int ; 2021: 6613439, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34337035

RESUMO

Methods: Immunohistochemical staining, sequencing, and genetic analysis of liver cancer tissues were performed. The antitumor efficacy of single-agent or combination treatment was measured by cell counting kit-8 assay and colony formation assays. Their antiproliferative and apoptosis activity is evaluated by cell cycle analyses and wound healing assays. The DNA-related proteins were also measured by Western blotting and immunohistochemical staining. The HepG2 xenograft model was used to detect the effects of lenvatinib-alisertib on the antitumor activity. Results: AURKA was found to be upregulated in HCC tissues (77.3%, 17/22). Combined alisertib and lenvatinib treatment significantly enhanced the inhibition of proliferation and migration in HepG2 and Hep3B cell lines compared to single-agent treatments (all Ps < 0.01). Alisertib alone or in combination with lenvatinib demonstrated a significant increase in the percentage of super-G2 cells (lenvatinib 1 µM vs. lenvatinib 1 µM + alisertib 0.1 µM 8.84 ± 0.84 vs. 34.0 ± 1.54, P < 0.001). Discontinuous spindles and missegregated chromosomes in HCC cells treated with alisertib in combination with lenvatinib were observed. We further revealed that combined treatment inhibited the expression of DNA damage pathway proteins compared to those of single-agent treatments. In nude mice, combined administration of alisertib combined with lenvatinib significantly enhanced the suppression of tumor growth and induced apoptosis (all Ps < 0.01). Conclusions: Our findings provide evidence for the possible use of alisertib in combination with lenvatinib in the treatment of HCC for better therapeutic outcomes.

16.
Med Res Rev ; 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34346083

RESUMO

Currently, the research of multi-omics, such as genomics, proteinomics, transcriptomics, microbiome, metabolomics, pathomics, and radiomics, are hot spots. The relationship between multi-omics data, drugs, and diseases has received extensive attention from researchers. At the same time, multi-omics can effectively predict the diagnosis, prognosis, and treatment of diseases. In essence, these research entities, such as genes, RNAs, proteins, microbes, metabolites, pathways as well as pathological and medical imaging data, can all be represented by the network at different levels. And some computer and biology scholars have tried to use computational methods to explore the potential relationships between biological entities. We summary a comprehensive research strategy, that is to build a multi-omics heterogeneous network, covering multimodal data, and use the current popular computational methods to make predictions. In this study, we first introduce the calculation method of the similarity of biological entities at the data level, second discuss multimodal data fusion and methods of feature extraction. Finally, the challenges and opportunities at this stage are summarized. Some scholars have used such a framework to calculate and predict. We also summarize them and discuss the challenges. We hope that our review could help scholars who are interested in the field of bioinformatics, biomedical image, and computer research.

17.
Cancers (Basel) ; 13(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34359777

RESUMO

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is an adenocarcinoma arising from the intrahepatic bile duct. It is the second most common primary liver cancer and has a poor prognosis. Activation of p53 by targeting its negative regulators, MDM2 and WIP1, is a potential therapy for wild-type p53 cancers, but few reports for iCCA or liver adenocarcinoma exist. METHODS: Both RBE and SK-Hep-1 liver adenocarcinoma cell lines were treated with the HDM201 (Siremadlin) MDM2-p53 binding antagonist alone or in combination with the GSK2830371 WIP1 phosphatase inhibitor. Cell proliferation, clonogenicity, protein and mRNA expression, cell cycle distribution, and RNA sequencing were performed to investigate the effect and mechanism of this combination. RESULTS: GSK2830371 alone demonstrated minimal activity on proliferation and colony formation, but potentiated growth inhibition (two-fold decrease in GI50) and cytotoxicity (four-fold decrease in IC50) by HDM201 on RBE and SK-Hep-1 cells. HDM201 increased p53 protein expression, leading to transactivation of downstream targets (p21 and MDM2). Combination with GSK2830371 increased p53 phosphorylation, resulting in an increase in both p53 accumulation and p53-dependent trans-activation. G2/M arrest was observed by flow cytometry after this treatment combination. RNA sequencing identified 21 significantly up-regulated genes and five downregulated genes following p53 reactivation by HDM201 in combination with GSK2830371 at 6 h and 24 h time points compared with untreated controls. These genes were predominantly known transcriptional targets regulated by the p53 signaling pathway, indicating enhanced p53 activation as the predominant effect of this combination. CONCLUSION: The current study demonstrated that GSK2830371 enhanced the p53-dependent antiproliferative and cytotoxic effect of HDM201 on RBE and SK-Hep-1 cells, providing a novel strategy for potentiating the efficacy of targeting the p53 pathway in iCCA.

18.
Blood ; 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34359074

RESUMO

Proper regulation of p53 signaling is critical for the maintenance of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs). The hematopoietic cell-specific mechanisms regulating p53 activity remain largely unknown. Here, we demonstrate that conditional deletion of acidic leucine-rich nuclear phosphoprotein 32B (ANP32B) in hematopoietic cells impairs repopulation capacity and post-injury regeneration of HSCs. Mechanistically, ANP32B forms a repressive complex with and thus inhibits the transcriptional activity of p53 in hematopoietic cells, and p53 deletion rescues the functional defect in Anp32b-deficient HSCs. Of great interest, ANP32B is highly expressed in leukemic cells from chronic myelogenous leukemia (CML) patients. Anp32b deletion enhances p53 transcriptional activity to impair LSCs function in a murine CML model, and exhibits synergistic therapeutic effects with tyrosine kinase inhibitors in inhibiting CML propagation. In summary, our findings provide a novel strategy to enhance p53 activity in LSCs by inhibiting ANP32B, and identify ANP32B as a potential therapeutic target in treating CML.

19.
Diagnostics (Basel) ; 11(7)2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34359287

RESUMO

Few prospective cohort trials have evaluated the potential risk factors of early treatment failure of locally advanced oral cavity squamous cell carcinoma (LAOCSCC) patients following the completion of postoperative adjuvant concurrent chemoradiotherapy (CCRT). We collected clinicopathological variables, nutrition-inflammatory markers and total body composition data assessed by dual-energy X-ray absorptiometry (DXA) before and after CCRT. A factor analysis was used to reduce the number of DXA-derived parameters. Cox proportional hazard models were applied to determine the risk factors associated with early treatment failure defined as tumor progression or death within 180 days of CCRT completion. A total of 69 patients were eligible for analysis. After CCRT, the body weight, body mass index, nutritional markers, and muscle mass decreased, whereas C-reactive protein level increased. Five factors reflecting different body composition statuses were identified. A total of 21 patients (30.4%) developed early treatment failure. Comorbidities (hazard ratio ((HR)), 2.699; 95% confidence interval ((CI)), 1.005-7.913; p = 0.044), radiation duration (HR, 1.092; 95% CI, 1.015-1.174; p = 0.018) and the pretreatment body muscle mass (HR, 0.578; 95% CI, 0.345-0.957; p = 0.037) independently contributed to early treatment failure. Comorbidities, longer radiation duration, and lower pretreatment body muscle mass are predictive factors for early treatment failure in LAOCSCC patients following postoperative adjuvant CCRT completion.

20.
Acta Radiol ; : 2841851211034035, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34382431

RESUMO

BACKGROUND: Open globe injury (OGI) is a serious condition that can lead to visual impairment and lifelong sequelae, brain activity of some brain regions would change in patients with OGI. PURPOSE: To evaluate changes in brain activity associated with unilateral OGI by resting-state functional magnetic resonance imaging (rs-fMRI) and analysis of percentage amplitude of fluctuation (PerAF). MATERIAL AND METHODS: A total of 22 patients with OGI (12 men, 10 women) and 22 healthy controls (HCs) matched for sex, age, and body weight were enrolled. All patients underwent rs-fMRI scans. Brain activity in the relevant brain regions was assessed with the PerAF method. The ability of PerAF to distinguish patients with OGI from HCs was assessed by receiver operating characteristic (ROC) curve analysis. We also examined the relationship between Hospital Anxiety and Depression Scale (HADS) scores and PerAF signals by Pearson's correlation analysis. RESULTS: PerAF values in amygdala_R and Frontal_Inf_Orb_L/Frontal_Inf_Oper_L were increased whereas that in Cerebellum Anterior Lobe/Cerebelum_8_L was decreased in patients with OGI compared to HCs. The areas under the ROC curve showed that these brain regions could distinguish between patients with OGI and HCs. The PerAF value of amygdala_R was positively correlated with HADS scores. CONCLUSION: Changes in PerAF in the amygdala_R, Frontal_inferior_Orb_L/Frontal_Inf_Oper_L, and Cerebellum Anterior Lobe/Cerebelum_8_L in patients with OGI may be related to an increased risk of developing psychiatric disorders such as anxiety and depression. PerAF can be used to investigate the neural basis of complications associated with OGI and monitor disease progression.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...